Zusammenfassung
Fortschritte in der medikamentösen Therapie des kolorektalen Karzinoms haben in den
letzten Jahren durch die Einführung neuer zytotoxischer Präparate zu einer signifikanten
Verbesserung der Behandlung von betroffenen Patienten geführt. Neue Erkenntnisse in
der molekularen Tumorbiologie führten zusätzlich zur Entwicklung einer Reihe von zielgerichteten,
tumorspezifischen monoklonalen Antikörpern, die sich nun in verschiedenen Stadien
der klinischen Erprobung befinden. Zwei dieser Antikörper, Cetuximab (Erbitux®) und
Bevacizumab (Avastin®), gerichtet gegen den Epidermal Growth Factor Receptor (EGFR)
bzw. den Vascular Epithelial Growth Factor (VEGF), wurden in der Zwischenzeit für
die Behandlung des metastasierten kolorektalen Karzinoms zugelassen. Die Kombination
von altbekannten und neuentwickelten Zytostatika mit monoklonalen Antikörpern hat
die medikamentöse Behandlung des kolorektalen Karzinoms zwar wesentlich komplexer
gemacht, bietet aber gerade Patienten mit Metastasen einen zusätzlichen Therapieansatz.
Abstract
Advances in the medical treatment of colorectal cancer patients have resulted in considerable
improvements through the introduction of new cytotoxic drugs. The significant progress
in molecular and tumour biology has produced a great number of targeted, tumour-specific,
monoclonal antibodies that are now in various stages of clinical development. Two
of these antibodies, cetuximab (Erbitux®) und bevacizumab (Avastin®), directed against
the epidermal growth factor receptor (EGFR) and the vascular epithelial growth factor
(VEGF), respectively, have recently been approved for use in metastatic colorectal
cancer. The combination of well-known and newly developed cytotoxic agents with monoclonal
antibodies makes the medical treatment of colorectal cancer patients considerably
more complex, but also provides additional therapeutic strategies for patients in
advanced stages of disease.
Schlüsselwörter
zielgerichtete Therapie - kolorektales Karzinom - EGFR - VEGF
Key words
targeted therapy - colorectal cancer - EGFR - VEGF
Literatur
1
Akbulut H, Altuntas F, Akbulut K G, Ozturk G, Cindoruk M, Unal E, Icli F.
Prognostic role of serum vascular endothelial growth factor, basic fibroblast growth
factor and nitric oxide in patients with colorectal carcinoma.
Cytokine.
2002;
20
184-190
2
Baselga J.
The EGFR as a target for anticancer therapy - focus on cetuximab.
Eur J Cancer.
2001;
37 Suppl 4
S16-S22
3
Chaudhary V K, Fitzgerald D J, Adhya S, Pastan I.
Activity of a recombinant fusion protein between transforming growth factor type alpha
and Pseudomonas toxin.
Proc Natl Acad Sci USA.
1987;
84
4538-4542
4
Ciardiello F, Caputo R, Troiani T, Borriello G, Kandimalla E R, Agrawal S, Mendelsohn J,
Bianco A R, Tortora G.
Antisense oligonucleotides targeting the epidermal growth factor receptor inhibit
proliferation, induce apoptosis, and cooperate with cytotoxic drugs in human cancer
cell lines.
Int J Cancer.
2001;
93
172-178
5
Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M,
Harstrick A, Verslype C, Chau I, Van Cutsem E.
Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic
colorectal cancer.
N Engl J Med.
2004;
351
337-345
6
de Gramont A, Bosset J F, Milan C, Rougier P, Bouche O, Etienne P L, Morvan F, Louvet C,
Guillot T, Francois E, Bedenne L.
Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with
bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for
advanced colorectal cancer: a French intergroup study.
J Clin Oncol.
1997;
15
808-815
7
Ellerbroek S M, Halbleib J M, Benavidez M, Warmka J K, Wattenberg E V, Stack M S,
Hudson L G.
Phosphatidylinositol 3-kinase activity in epidermal growth factor-stimulated matrix
metalloproteinase-9 production and cell surface association.
Cancer Res.
2001;
61
1855-1861
8
Fan Z, Lu Y, Wu X, Mendelsohn J.
Antibody-induced epidermal growth factor receptor dimerization mediates inhibition
of autocrine proliferation of A 431 squamous carcinoma cells.
J Biol Chem.
1994;
269
27595-27602
9
Ferrara N, Gerber H P, LeCouter J.
The biology of VEGF and its receptors.
Nat Med.
2003;
9
669-676
10
Folkman J.
Angiogenesis in cancer, vascular, rheumatoid and other disease.
Nat Med.
1995;
1
27-31
11
Gordon M S, Cunningham D.
Managing patients treated with bevacizumab combination therapy.
Oncology.
2005;
69 Suppl 3
25-33
12
Gordon M S, Margolin K, Talpaz M, Sledge Jr G W, Holmgren E, Benjamin R, Stalter S,
Shak S, Adelman D.
Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial
growth factor in patients with advanced cancer.
J Clin Oncol.
2001;
19
843-850
13
Gross M E, Zorbas M A, Danels Y J, Garcia R, Gallick G E, Olive M, Brattain M G, Boman B M,
Yeoman L C.
Cellular growth response to epidermal growth factor in colon carcinoma cells with
an amplified epidermal growth factor receptor derived from a familial adenomatous
polyposis patient.
Cancer Res.
1991;
51
1452-1459
14
Grothey A, Sargent D, Goldberg R M, Schmoll H J.
Survival of patients with advanced colorectal cancer improves with the availability
of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment.
J Clin Oncol.
2004;
22
1209-1214
15
Heinzerling J H, Huerta S.
Bowel perforation from Bevacizumab for the treatment of metastatic colon cancer: incidence,
etiology, and management.
Curr Surg.
2006;
63
334-337
16
Hochster H S, Hart L L, Ramanathan R K, Hainsworth J D, Hedrick I I, Childs B H.
Safety and efficacy of oxaliplatin / fluoropyrimidine regimens with or without bevacizumab
as first-line treatment of metastatic colorectal cancer: final analysis of the TREE-study.
J Clin Oncol.
2006;
24
3510
, ASCO Annual Meeting Proceedings Part I Vol 24 No 18 S (June 20 supplement)
17
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J,
Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F.
Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal
cancer.
N Engl J Med.
2004;
350
2335-2342
18
Italiano A.
Targeting the epidermal growth factor receptor in colorectal cancer: advances and
controversies.
Oncology.
2006;
70
161-167
19
Kabbinavar F, Hurwitz H I, Fehrenbacher L, Meropol N J, Novotny W F, Lieberman G,
Griffing S, Bergsland E.
Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU) / leucovorin
(LV) with FU / LV alone in patients with metastatic colorectal cancer.
J Clin Oncol.
2003;
21
60-65
20
Kang S M, Maeda K, Onoda N, Chung Y S, Nakata B, Nishiguchi Y, Sowa M.
Combined analysis of p53 and vascular endothelial growth factor expression in colorectal
carcinoma for determination of tumor vascularity and liver metastasis.
Int J Cancer.
1997;
74
502-507
21
Khorana A A, Ryan C K, Cox C, Eberly S, Sahasrabudhe D M.
Vascular endothelial growth factor, CD 68, and epidermal growth factor receptor expression
and survival in patients with Stage II and Stage III colon carcinoma: a role for the
host response in prognosis.
Cancer.
2003;
97
960-968
22
Koenders P G, Peters W H, Wobbes T, Beex L V, Nagengast F M, Benraad T J.
Epidermal growth factor receptor levels are lower in carcinomatous than in normal
colorectal tissue.
Br J Cancer.
1992;
65
189-192
23
Kohne C H, Folprecht G.
Current perspectives in the treatment of metastatic colorectal cancer.
Ann Oncol.
2004;
15 Suppl 4
iv 43-iv 53
24
Lee J C, Chow N H, Wang S T, Huang S M.
Prognostic value of vascular endothelial growth factor expression in colorectal cancer
patients.
Eur J Cancer.
2000;
36
748-753
25
Lin Y S, Nguyen C, Mendoza J L, Escandon E, Fei D, Meng Y G, Modi N B.
Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of a humanized
monoclonal antibody against vascular endothelial growth factor.
J Pharmacol Exp Ther.
1999;
288
371-378
26
Lockhart A C, Berlin J D.
The epidermal growth factor receptor as a target for colorectal cancer therapy.
Semin Oncol.
2005;
32
52-60
27
McKay J A, Murray L J, Curran S, Ross V G, Clark C, Murray G I, Cassidy J, McLeod H L.
Evaluation of the epidermal growth factor receptor (EGFR) in colorectal tumours and
lymph node metastases.
Eur J Cancer.
2002;
38
2258-2264
28
Mendelsohn J, Baselga J.
Status of epidermal growth factor receptor antagonists in the biology and treatment
of cancer.
J Clin Oncol.
2003;
21
2787-2799
29
Meropol N J, Berlin J D, Hecht J R, Croghan G A, Patnaik A, Weiner L M, Sweed M, Wiens B L,
Caron D, Visonneau S.
Multicenter study of ABX-EGF monotherapy in patients with metastatic colorectal cancer.
Proc Am Soc Clin Oncol.
2003;
22 (abstr 1026)
30 National Institute for Health and Clinical Excellence .Final appraisal determination,
Bevacizumab and cetuximab for metastatic colorectal cancer. www.nice.org.uk 2006
31
Ozawa S, Ueda M, Ando N, Abe O, Minoshima S, Shimizu N.
Selective killing of squamous carcinoma cells by an immunotoxin that recognizes the
EGF receptor.
Int J Cancer.
1989;
43
152-157
32
Peeters M, Van Cutsem E, Siena S, Humblet Y, Hendlisz A, Neyns J, Canon J, Van Laethem M,
Amado R.
A phase 3, multicenter, randomized controlled trial of panitumumab plus best supportive
care (BSC) vs. BSC alone in patients with metastatic colorectal cancer.
Proc Am Soc Clin Oncol.
2006;
abstr 3548
33
Perrotte P, Matsumoto T, Inoue K, Kuniyasu H, Eve B Y, Hicklin D J, Radinsky R, Dinney C P.
Anti-epidermal growth factor receptor antibody C 225 inhibits angiogenesis in human
transitional cell carcinoma growing orthotopically in nude mice.
Clin Cancer Res.
1999;
5
257-265
34
Prewett M C, Hooper A T, Bassi R, Ellis L M, Waksal H W, Hicklin D J.
Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody
IMC-C 225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts.
Clin Cancer Res.
2002;
8
994-1003
35
Radinsky R, Risin S, Fan D, Dong Z, Bielenberg D, Bucana C D, Fidler I J.
Level and function of epidermal growth factor receptor predict the metastatic potential
of human colon carcinoma cells.
Clin Cancer Res.
1995;
1
19-31
36
Raymond E, Faivre S, Armand J P.
Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy.
Drugs.
2000;
60 Suppl 1
15-23
37
Rougier P, Raoul J VLM, Mueser M.
Cetuximab and FOLFIRI as first-line treatment for metastatic colorectal CA.
J Clin Oncol.
2004;
22
3
, ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 145 (July 15
Supplement), 2004: 3
38
Roy H, Bhardwaj S, Yla-Herttuala S.
Biology of vascular endothelial growth factors.
FEBS Lett.
2006;
580
2879-2887
39
Saltz L B, Meropol N J, Loehrer Sr P J, Needle M N, Kopit J, Mayer R J.
Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses
the epidermal growth factor receptor.
J Clin Oncol.
2004;
22
1201-1208
40
Tabernero J, Van Cutsem E, Sastre J, Cervantes A, Mueser M.
An international phase II study of cetuximab in combination with oxaliplatin / 5-FU
/ folinic acid (FOLFOX 4) in the first-line treatment of patients with metastatic
colorectal cancer expressing Epidermal Growth Factor Receptor. Preliminary results.
J Clin Oncol.
2004;
22
39
, ASCO Annual Meeting Proceedings (Post Meeting Edition) Vol 22, No 145 (July 15
Supplement), 2004: 39
41
Takahashi Y, Kitadai Y, Bucana C D, Cleary K R, Ellis L M.
Expression of vascular endothelial growth factor and its receptor, KDR, correlates
with vascularity, metastasis, and proliferation of human colon cancer.
Cancer Res.
1995;
55
3964-3968
42
Thirion P, Michiels S, Pignon J P, Buyse M, Braud A C, Carlson R W, O'Connell M, Sargent P,
Piedbois P.
Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer:
an updated meta-analysis.
J Clin Oncol.
2004;
22
3766-3775
43
Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C,
Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A.
FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer:
a randomized GERCOR study.
J Clin Oncol.
2004;
22
229-237
44
Tyagi P.
Vatalanib (PTK787 / ZK 222584) in combination with FOLFOX4 versus FOLFOX4 alone as
first-line treatment for colorectal cancer: preliminary results from the CONFIRM-1
trial.
Clin Colorectal Cancer.
2005;
5
24-26
45
Warren R S, Yuan H, Matli M R, Gillett N A, Ferrara N.
Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis
in a mouse model of experimental liver metastasis.
J Clin Invest.
1995;
95
1789-1797
46
Weiner L M.
Updated results from a dose and schedule study of Panitumumab monotherapy in patients
with advanced solid malignancies.
Proc Am Soc Clin Oncol.
2005;
abstr 3059
47
Wu X, Fan Z, Masui H, Rosen N, Mendelsohn J.
Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody
in a human colorectal carcinoma cell line and its delay by insulin.
J Clin Invest.
1995;
95
1897-1905
Dr. med. A. Thalheimer
Chirurgische Klinik und Poliklinik I · Zentrum Operative Medizin der Universitätsklinik
Würzburg
Oberdürrbacher Str. 6
97080 Würzburg
Telefon: 09 31 / 20 11
eMail: Thalheimer_A@chirurgie.uni-wuerzburg.de